6Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Corresponding author: David K.C. Cooper, cooperdk{at}upmc.edu.

D.J.v.d.W. and R.B. contributed equally to this study.

Type 1 diabetes (T1D) is a major health problem throughout the world. In the U.S., it is estimated that about 1.5 million
people suffer from T1D. Even when well controlled—by frequent monitoring of blood glucose and administration of insulin, the
long-term complications of the disease are significant and include cardiovascular disease, nephropathy, retinopathy, and neuropathy
(1). Here we review recent progress in preclinical models of pig islet xenotransplantation and discuss the remaining challenges
that need to be addressed before the application of this form of therapy can be established in patients with T1D.

During the past decade, islet allotransplantation alone (without previous kidney transplantation) using deceased human donor
pancreata has been indicated mainly in patients who have had T1D for >5 years with life-threatening hypoglycemic episodes
and wide fluctuations in blood glucose levels. Although the initial long-term results were rather disappointing (2), the results of islet allotransplantation have improved significantly in recent years, with 5-year insulin-independent normoglycemia
achieved in >50% of patients at experienced centers (3). There is increasing evidence that successful islet allotransplantation greatly reduces the incidence of hypoglycemic episodes
(2) and reduces or slows the incidence of late complications of T1D (4). This may extend the indications for islet transplantation to patients with progressive complications. For example, islet
transplantation in a patient with preterminal renal failure may prevent disease progression, possibly avoiding the need for
hemodialysis and kidney transplantation, provided that nonnephrotoxic immunosuppressive drug therapy is administered.

Currently, in the U.S., the median waiting time for a kidney allograft from a deceased human donor is >4 years (5). However, islets from two deceased human donor pancreata are frequently required to achieve normoglycemia in a diabetic
patient. Because of the limited number of suitable deceased donor pancreata, the overall number of …